Researchers discover a new immune target for heart disease treatment
The protein, called suPAR, has long been known to be a biomarker of poor outcomes and disease progression in both kidney disease and cardiovascular disease.
A new study led by researchers at Michigan Medicine found a protein produced by the immune system that causes atherosclerosis, which could lead to promising new treatments, according to the authors.
Doctors have long treated cardiovascular disease by focusing on diabetes and blood pressure control, using drugs like aspirin and cholesterol-lowering statins. Despite the effectiveness of these approaches, heart disease is the No. 1 cause of death in the United States, and many patients experience heart attacks even with controlled risk factors.
Researchers have now discovered a protein, called soluble urokinase plasminogen activator receptor (suPAR), that could be a promising alternative. The protein acts as a regulator of immune system activity, which has long been considered a key focus for this treatment space. This research marks the first evidence showing that suPAR causes atherosclerosis when at high levels.
“Targeting the immune component central to the development of atherosclerosis is the Holy Grail for treating heart disease,” said lead author Salim Hayek, MD, in a news release. “This is the first time that a component of the immune system has been identified that meets all the requirements to be a promising treatment target for atherosclerosis.”
The study findings have 3 key parts. First, the research team looked at the Multi-Ethnic Study of Atherosclerosis and found that people with higher levels of suPAR were much more likely to develop atherosclerosis and experience cardiovascular events, regardless of their underlying risk factors.
Next, the researchers conducted a genetic study of 24,000 people to determine if certain genetic variations affected suPAR levels in the blood. They found a specific variant in the PLAUR gene that codes for suPAR, and participants with that gene variant tended to have higher levels of suPAR. Importantly, this genetic variant was associated with atherosclerosis in a Mendelian randomization analysis of 500,000 participants in the UK Biobank, which was replicated in 2 other large data sets.
“We also found that participants who lacked a copy of the PLAUR they have a lower risk of heart disease,” said first author and geneticist George Hindy, MD, PhD, in the news release. “Taken together, the genetic data is really compelling that high suPAR is a cause of atherosclerosis.”
Finally, in mouse models with high suPAR levels, the researchers observed a dramatic increase in atherosclerotic plaques in the aortas of the mice compared to mice with normal suPAR levels.
“Even before developing atherosclerosis, mouse aortas with high suPAR levels contained more inflammatory white blood cells, and immune cells circulating in the blood were in an activated state, or ‘attack mode,'” said co-author Daniel Tyrrell, PhD. . in the press release. “It appears that high suPAR levels activate immune cells and prime them to overreact to the high cholesterol environment, causing these cells to enter the blood vessel wall and accelerate the development of atherosclerosis.” .
Interestingly, Hayek noted that this research highlighted high-quality clinical, genetic, and experimental data, all of which point to suPAR as a cause of atherosclerotic disease. Additionally, research has found that suPAR is a pathogenic factor that causes kidney disease, which affects 1 in 7 Americans.
Patients often experience both conditions, and two-thirds of those with kidney disease also experience cardiovascular disease. Similarly, more than 40% of patients with cardiovascular disease have signs of kidney disease.
“This article positions suPAR as the link between renal and cardiovascular disease; a common factor that causes both through this inappropriate and persistent activation of the immune system,” said co-author Jochen Reiser, MD, PhD, in the news release. “This is pointed out in the researchers’ Mendelian randomization genetic analysis, which shows that a high suPAR level is also associated with kidney disease.”
SuPAR has long been known to be a biomarker of poor outcome and disease progression in both renal disease and cardiovascular disease. A 2020 study found that suPAR can worsen acute kidney injury, and that suPAR blockade prevents it. A more recent study also found that protein levels are high in heart failure patients and predict the patients’ death.
With this growing body of knowledge, suPAR has the potential to be a successful treatment target for cardiovascular and renal diseases.
“My hope is that we can provide these treatments to our patients within the next 3 to 5 years,” Hayek said in the news release. “This will be a game changer for the treatment of atherosclerotic and kidney disease.”
REFERENCE
New immune target discovered to treat cardiovascular diseases. Press release. Michigan Medicine; December 15, 2022. Accessed January 4, 2023. https://labblog.uofmhealth.org/lab-report/new-immune-target-to-treat-cardiovascular-disease-discovered